Our goal has been to explore the neural basis and pathogenesis of two common, disabling and closely related movement disorders, dystonia and parkinsonism. We have pursued this goal by studying in rodent models the effect of early striatal injury, either hypoxic-ischemic (H-1) or excitotoxic, on the subsequent development of the striatum and its major source of dopaminergic afferents, the substantia nigra (SN). Our work under NS26836 has shown that following either H-I or excitotoxic injury to the developing striatum there is preservation of dopaminergic terminal markers by morphologic and biochemical criteria. In spite of the preservation of these markers in striatum, the subsequent development of the SN is abnormal; the number of dopaminergic neurons is markedly reduced, directly in correlation with the degree of reduction in striatal target size. This reduction occurs in the absence of direct H-I or excitotoxic injury to the SN. In this proposal we will explore the hypothesis that the decrease in the number of SN neurons is due to diminished target-derived support from the striatum, and specifically that diminished support results in an induced developmental cell death event in SN, with characteristics of apoptosis. In support of this hypothesis, we have shown that developmental cell death occurs in postnatal SNpars compacta (SNpc). In our first Specific Aim we will determine whether an induced cell death event occurs in SN following early excitotoxic striatal injury, and whether the death meets morphologic and biochemical criteria for apoptosis. We will establish the time course of induced death in SNpc and SNpars reticulata, and, by immunohistochemistry, define the phenotype of the dying cells. Secondly, we will characterize the time course, regional distribution and cellular phenotype of natural cell death prenatally in SN. In our third Aim, we will determine whether there is an age dependence of striatal support of the SN. Our hypothesis would predict that, if reduced striatal target size results in an induced cell death event in SN, then, conversely, an augmented target size or availability of trophic factors will result in a diminished death event. This prediction will be studied in Aim IV, using implantation of additional exogenous striatal tissue, early striatal injection of two neurotrophins, BDNF and NT-3, and implantation of BDNF-producing fibroblasts. We will also determine whether BDNF or NT-3 will attenuate the induced cell death caused by early striatal excitotoxic injury. Finally, we will use in situ hybridization to explore whether the molecular events underlying apoptosis in SN are similar to those observed in peripheral systems where a cascade of c-fos to c-myc to hsp-70 has been observed. We will also determine whether the cell cycle-blocking agent p53 and the sulfated glycoprotein TRPM-2 are expressed during induced SN cell death, as they are in apoptosis in peripheral tissue. This proposal represents an important and novel approach to the pathogenesis of Parkinson's Disease in that it considers the possible role of genetically-mediated, programmed cell death in the degeneration of nigral dopaminergic neurons.